VEGF/Neuropilin-2 Signaling and Radioresistance in Triple-Negative Breast Cancer

三阴性乳腺癌中的 VEGF/Neuropilin-2 信号转导和放射抗性

• 批准号: 10678449
• 负责人: Ayush Kumar
• 金额: $ 3.49万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-28 至 2027-03-27
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678449
• 关键词: Adjuvant Chemotherapy; Antioxidants; Binding; Blocking Antibodies; Breast Cancer Cell; Breast Cancer Patient; Breast-Conserving Surgery; Cell Death; Cell Survival; Cells; DNA Damage; Data; Effectiveness; Extinction; Failure; Fellowship; Gene Expression Profile; Genes; Genetic Transcription; Goals; Growth; Homeostasis; In complete remission; Literature; Mediating; Metabolic; Metabolic Pathway; Molecular; Nature; Neoadjuvant Therapy; Neuropilin-2; Nitric Oxide; Nitric Oxide Synthase; Nuclear; Organoids; Oxidation-Reduction; Oxidative Stress; Oxidative Stress Induction; Pathologic; Pathway interactions; Patients; Phenotype; Physicians; Population; Prognosis; Property; Radiation; Radiation Tolerance; Radiation therapy; Reactive Inhibition; Reactive Oxygen Species; Recurrence; Regulation; Research; Residual Neoplasm; Resistance; Role; Scientist; Signal Induction; Signal Transduction; Surgical Management; Survival Rate; Technology; Testing; Therapeutic; Training; Variant; Vascular Endothelial Growth Factors; Vascular Endothelium; bench to bedside; cancer stem cell; cancer subtypes; carcinogenesis; clinically significant; effectiveness evaluation; improved; in vivo Model; insight; irradiation; knock-down; malignant breast neoplasm; molecular subtypes; neoplastic cell; novel; novel therapeutic intervention; patient derived xenograft model; pre-clinical; radiation resistance; radioresistant; receptor; relapse patients; relapse prevention; resistance mechanism; response; self-renewal; single-cell RNA sequencing; stem cells; targeted treatment; therapeutic target; therapy outcome; therapy resistant; traditional therapy; treatment response; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor heterogeneity

PROJECT SUMMARY Triple Negative Breast Cancer (TNBC) is an aggressive form of breast cancer with standard therapy involving neoadjuvant chemotherapy, surgical management, and radiation therapy. However, the high recurrence rate and low pathological complete response of TNBC suggest that radioresistance is a critical factor in the diminished therapeutic efficiency of the current treatment strategy. There is limited literature exploring the specific pathways responsible for radiation resistance in TNBC, but most data support the role of limiting reactive oxygen species (ROS) accumulation. Our lab has studied the role of Vascular Endothelia Growth Factor (VEGF) binding to Neuropilin-2 (NRP2) and initiating several cancer stem cell properties. Preliminary data indicate that radiation enriches for NRP2 expressing cells and using a function blocking antibody specific to VEGF/NRP2 with irradiation decreases cell viability compared to either treatment alone in a TNBC organoid. The central hypothesis of this proposal is that VEGF/NRP2 induces radioresistance by altering redox homeostasis and can be targeted for better therapeutic outcomes in TNBC. This proposal will seek to investigate a possible role of NRP2 regulating NOS2 transcription and its contribution to mitigating ROS accumulation. I will also use single-cell RNA sequencing technology to identify the subpopulations of TNBC that are radioresistant and whether they utilize the NRP2/NOS2 signaling axis. Another aspect of this proposal is to observe the effectiveness of a function blocking antibody of NRP2 with radiation using an in vivo model. I plan to identify if this approach reduces the radioresistant clones in TNBC. The completion of this proposal will heighten the understanding of radioresistance in TNBC and identify a novel molecular pathway responsible for this phenotype.

项目概要 三阴性乳腺癌 (TNBC) 是一种侵袭性乳腺癌，标准治疗包括 新辅助化疗、手术治疗和放射治疗。但复发率高且 TNBC 的低病理完全缓解表明放射抗性是 TNBC 减弱的关键因素。 当前治疗策略的治疗效果。探索具体途径的文献有限 负责 TNBC 的抗辐射性，但大多数数据支持限制活性氧的作用 （ROS）积累。我们的实验室研究了血管内皮生长因子 (VEGF) 结合的作用 Neuropilin-2 (NRP2) 并启动多种癌症干细胞特性。初步数据表明，辐射 富集 NRP2 表达细胞并使用针对 VEGF/NRP2 的功能阻断抗体 与单独处理 TNBC 类器官中的任何一种治疗相比，辐射会降低细胞活力。中央 该提议的假设是 VEGF/NRP2 通过改变氧化还原稳态来诱导放射抗性 可以针对 TNBC 获得更好的治疗结果。该提案将寻求调查可能的 NRP2 调节 NOS2 转录的作用及其对减轻 ROS 积累的贡献。我也会用 单细胞 RNA 测序技术可鉴定具有抗辐射性和抗辐射性的 TNBC 亚群 他们是否利用 NRP2/NOS2 信号轴。该提案的另一个方面是遵守 使用体内模型研究 NRP2 功能阻断抗体对辐射的有效性。我打算确定是否 这种方法减少了 TNBC 中的抗辐射克隆。该提案的完成将进一步提升 了解 TNBC 的放射抗性并确定导致该表型的新分子途径。